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Lead optimization of 1,4-azaindoles as antimycobacterial agents
Pravin S Shirude1, Radha K Shandil, M R Manjunatha
1Department of Medicinal Chemistry, iMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
Abstract:
In a previous report, we described the discovery of 1,4-azaindoles, a chemical series with excellent in vitro and in vivo antimycobacterial potency through noncovalent inhibition of decaprenylphosphoryl-β-d-ribose-2'-epimerase (DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase 6 (PDE6) off-target activity limited its advancement. Herein, we report lead optimization of this series, culminating in potent, metabolically stable compounds that have a robust pharmacokinetic profile without any PDE6 liability. Furthermore, we demonstrate efficacy for 1,4-azaindoles in a rat chronic TB infection model. We believe that compounds from the 1,4-azaindole series are suitable for in vivo combination and safety studies.
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